The present work will provide new insights into how drugs bind to and activate a family of receptors that are found throughout the central and peripheral nervous systems. These receptors are called Cys-loop receptors, and they are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, pain, epilepsy, ADHD, autism, depression, addiction and more. Using powerful methodologies developed in previous years of the grant, the structures of the receptors can be modified in precise and subtle ways. In particular, the amino acids that are the building blocks of these protein receptors can be specifically replaced with designed, unnatural amino acids. This allows unprecedented control over the functionality present. How these modifications impact the effectiveness of drugs that target the receptor provides key insights into the mechanism of drug action. A key issue to be addressed will be receptor selectivity - how certain drugs are able to target only specific members of a collection of very closely related receptors. The knowledge generated from these studies will be very valuable to efforts to develop new pharmaceuticals to address the many neurological disorders associated with malfunctions of the Cys-loop receptors. PUBLIC HEALTH RELEVANCE: Neurological disorders, including unipolar depressive disorders, bipolar affective disorder, and schizophrenia, present the greatest health hazard to adults in developed countries, according to the World Health Organization Global Burden of Disease assessment. The present work will provide new insights into how drugs bind to and activate a family of receptors found throughout the central and peripheral nervous systems. Malfunctions of these receptors are associated with the full spectrum of neurological disorders, and knowledge generated by this grant will be of great value to efforts to develop new pharmaceuticals to combat these dreaded diseases.